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ProNGF promotes brain metastasis through TrkA/EphA2 induced Src activation in triple negative breast cancer cells

Julien Cicero1,2,3, Sarah Trouvilliez1,3, Martine Palma1,3

  • 1UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France.

Experimental Hematology & Oncology
|December 10, 2023
PubMed
Abstract

Insights

The precursor of Nerve Growth Factor (proNGF) drives brain metastasis in Triple-Negative Breast Cancer (TNBC) by affecting the blood-brain barrier. Targeting the TrkA/EphA2 complex offers a potential therapeutic strategy for TNBC brain metastasis.

Area of Science:

  • Oncology
  • Neuroscience
  • Cancer Metastasis

Background:

  • Triple-Negative Breast Cancer (TNBC) is aggressive, with brain metastasis significantly impacting patient survival and quality of life.
  • Mechanisms driving TNBC brain metastasis remain poorly understood, necessitating further research.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying TNBC brain metastasis.
  • To identify novel therapeutic targets for preventing or treating brain metastasis in TNBC.

Main Methods:

  • Utilized a combination of in vitro (human blood-brain barrier model, 3D organotypic matrix) and ex vivo (mouse brain slices) models, along with in vivo xenograft experiments.
  • Investigated the role of the precursor of Nerve Growth Factor (proNGF) and its signaling pathways in TNBC brain metastasis.

Main Results:

  • Demonstrated the involvement of proNGF in TNBC brain metastasis, acting independently of TrkA phosphorylation.
  • Identified the TrkA/EphA2 signaling complex as crucial for proNGF-induced blood-brain barrier transmigration.
  • Showed that combined inhibition of TrkA and EphA2 reduced TNBC brain metastasis in a preclinical model.

Conclusions:

  • proNGF is a key driver of TNBC brain metastasis.
  • The TrkA/EphA2 signaling complex represents a promising therapeutic target for TNBC brain metastasis.
Keywords:
Brain metastasisBreast cancerEphA2SrcTrkAproNGF

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